The goal of this study is to determine the molecular mechanisms responsible for initiation and maintenance of torpor (hypothermia, bradycardia, and reduced physical activity) in hibernating mammals. The central hypothesis of this study is that the naturally occurring, thyroid hormone derivative 3-iodothyronamine (T1AM) plays a key role in initiating and maintaining torpor in hibernating mammals. This hypothesis is based on the observation that mice injected with T1 AM enter a temporary state of torpor that is strikingly similar to natural hibernation [7, 8]. These results suggest that T1 AM may be a promising pharmacological agent for induction of therapeutic hypothermia in humans. To test the above hypothesis I propose the following three specific aims using the naturally hibernating thirteen-lined ground squirrel, Spermophilus tridecemlineatus. 1. Measure the endogenous concentration of the thyroid hormone derivative 3-iodothyronamine (T1 AM) and the thyroid hormones thyroxine (T4) and 3, 5, 3'-triiodothyronine (T3) in serum and tissues of thirteenlined ground squirrels before, during, and after hibernation. 2. Determine if a hibernation-like phenotype can be initiated in thirteen-lined ground squirrels at different times of the year in a natural hibernator by artificially raising the circulating T1AM concentration. 3. Determine if the molecular and metabolic phenotype of natural hibernation torpor is duplicated when the circulating concentration of T1AM is raised artificially. Importance and relevance. The adaptive strategies of hibernators are applicable to human health situations such as body cooling, transplantation of organs, hemorrhagic shock, and oxidative tissue damage resulting from stroke and reperfusion injury. Substantial information already exists showing that natural hibernators tolerate prolonged hypoxia and hypothermia [57-59]. Information gathered from the study of natural hibernators is directly transferable to human health because hibernation occurs by novel regulation of molecular genetic and physiological pathways that are common to all mammals.